NF-kB control of neuronal apoptosis in Alzheimer disease

2011财年，我们完成了以下工作： 1.完成了COX2抑制剂调节细胞死亡和炎症的机制研究。我们的观察表明，塞来昔布通过COX2依赖的途径促进活化的CD4T细胞的凋亡。相反，塞来昔布通过COX2非依赖性途径抑制促炎性肿瘤坏死因子超家族受体和配体的表达。塞来昔布的抗炎作用是通过抑制核因子B家族成员REL来实现的。因此，缺乏REL的CD4T细胞在许多方面与塞来昔布治疗的细胞相似。 2.我们进一步扩展了上述塞来昔布研究，以测试另外四种COX2抑制剂。根据塞来昔布的研究，其中两种抑制剂影响细胞死亡并干扰REL的诱导，而另外两种对REL的诱导或肿瘤坏死因子超家族受体和配体的表达没有影响。这些观察表明，Coxibs的抗炎作用的一个主要机制是通过抑制Rel。

During fiscal year 2011, we accomplished the following: 1. Completed studies on the mechanism of COX2 inhibitors in regulating cell death and inflammation. Our observations demonstrate that celecoxib accentuates apoptosis of activated CD4+ T cell blasts via a COX2-dependent pathway. In contrast, celecoxib inhibits expression pro-inflammatory TNF super-family receptors and ligands via a COX2-independent pathway. The anti-inflammatory effects of celecoxib are mediated via suppression of the NF-κB family member, Rel. Accordingly, Rel-deficient CD4+ T cell blasts resemble celecoxib-treated blasts in many respects. 2. We further extended the celecoxib studies described above to test four additional COX2 inhibitors. Two of these inhibitors affected cell death and interfered with Rel induction as noted for celecoxib, whereas the other two had no effect on Rel-induction or expression of TNF superfamily receptors and ligands. These observations indicate that a major mechanism of anti-inflmmatory effects of coxibs is via suppression of Rel.